The present invention relates to the organic chemistry field.
More particularly, the invention relates to a process for the preparation of 2-(4-methylphenyl)benzoic acid esters.
2-(4-Methylphenyl)benzoic acid is a useful intermediate for the synthesis of 2-(4-methylphenyl)-benzonitrile, also known under the name OTBN (ortho-toluylbenzonitrile), and/or of the corresponding tetrazolyl derivative MBT, which, as it is illustrated in the following Scheme 1, are in their turn key intermediates in the synthesis of xe2x80x9cSartansxe2x80x9d, which are angiotensin II antagonistic compounds used as antihypertensives. 
A number of methods for the preparation of OTBN are available, as reported in Chemistry Today, 1998, March/April, 18 and in Specialty Chem., 1998, 436, and as summarized in Scheme 2. 
Said methods are described in Angew. Chem.Int.Ed.Engl., 1995, 34, 1844; J.Org.Chem., 1999, 64, 10; Tetrahedron Lett. 1998, 39, 6441; Tetrahedron Lett., 1999, 40, 197.
The syntheses according to Suzuki and Negishi (Scheme 2), though efficient, start from 2-bromobenzonitrile, a very expensive commercial reagent. On the other hand, the synthesis according to Meyers starts from less costly 2-methoxybenzoic acid, but it involves a high number of chemical steps. Recent works exist (see the above cited documents) concerning the preparation of OTBN, through cross-coupling organometal reactions between 4-methylphenyl-metal derivatives and the less expensive 2-chlorobenzonitrile catalyzed by palladium (0) and nickel (0).
Particularly interesting is the Clariant process for the synthesis of OTBN starting from 2-chlorobenzonitrile and 4-methylphenylboronic acid by means of the Suzuki reaction reported in Scheme 3. 
Alternatively to the direct preparation of OTBN starting from benzonitrile precursors, a cross-coupling reaction starting from the corresponding benzoic esters has also been studied.
For example, the reaction of 4-bromotoluene and methyl 2-chlorobenzoate in the presence of NiCl2, PPh3 and zinc powder in pyridine at 80xc2x0 C. yields the corresponding biphenyl derivatives with low selectivity. (Scheme 4) (Synlett, 1994, 371). 
Methyl 2-(4-methylphenyl)-benzoate has recently been obtained in a 47% yield, i.e. with low selectivity, by the Ni-mediated cross-coupling reaction between 4-methylphenylboronic acid and methyl 2-methanesulfonyloxybenzoate (Scheme 5) (Tetrahedron, 1998, 54, 13079). 
Methyl 2-methanesulfonyloxybenzoate is easily prepared starting from methyl salicylate, a derivative available in large amounts at very low costs. However, the low selectivity of the cross-coupling reaction with 4-methoxy-phenylboronic acid does not advantageously yields the bi-phenyl derivative.
Generally speaking, the cross-coupling reactions between an arylsulfonate and organozinc derivatives catalyzed by nickel (0) are known to result in low selectivity (Scheme 6) (J.Org.Chem. 1995, 60, 6895). 
The present invention aims at providing a process for the preparation of 2-(4-methylphenyl)benzoic acid esters in good yields starting from inexpensive starting materials.
Therefore, the invention provides a process for the preparation of 2-(4-methylphenyl)benzoic acid esters of formula (I) 
wherein R is C1-6alkyl, comprising the reaction of a sulfonic derivative of formula (II) 
wherein R is as defined above and R1 is selected from the group consisting of optionally perfluorinated C1-6alkyl and optionally substituted C6-10aryl, with an arylzinc compound of formula (III) 
wherein X is a halogen selected from chlorine, bromine and iodine, in an organic solvent and in the presence of a catalyst based on palladium (0) or nickel (0).
The catalyst is preferably selected from the group consisting of elementary Pd or Ni (metal, cluster etc.) optionally supported (for example on charcoal), Pd or Ni complexes with ligands both preformed and generated in situ by reduction of Pd(II) or Ni(II) salts in the presence of ligands. The latter are preferably selected from the group consisting of phosphorous (III) derivatives, such as triphenylphosphine, tritolyphosphine, tributylphosphine, 1,2-bis-diphenylphosphinoethane and bis-diphenylphosphino-ferrocene. The reduction can be carried out using, for example, magnesium, zinc, alkyllithium, in particular n-butyllithium, triethylamine, triphenylphosphine and the like.
Examples of suitable Pd and Ni salts are Pd acetate, Pd chloride, Ni acetate, Ni chloride.
Examples of Pd and Ni complexes are bis-(triphenylphosphino)-dichloro; bis-(tributylphosphino)-dichloro; tetrakis-(triphenylphosphine); triphenylphosphino-piperidine-dichloro; bis-(triphenylphosphine)-diacetate; 1,2-bis-(diphenylphosphino)-ethane complexes.
The substituent R1 is preferably selected from the group consisting of perfluoroethyl, perfluorobutyl, perfluoroctyl, 4-methylphenyl, 4-nitrophenyl, 2-naphthyl and 1-naphthyl.
The organic solvent used in the reaction is preferably selected from the group consisting of aromatic hydrocarbons, in particular toluene and xylene, and aliphatic ethers, particularly methyl tert-butyl ether, or alicyclic hydrocarbons, in particular tetrahydrofuran, and mixtures thereof. The solvent is used in amounts ranging between 1 and 10 volumes, preferably between 2 and 5 volumes, compared with the compound of formula (II).
The reaction is generally carried out at temperatures ranging from 0xc2x0 to 150xc2x0 C., preferably from 20 to 80xc2x0 C., using 1 to 2, preferably 1.2 to 1.5, equivalents of arylzinc of formula (III) per equivalent of sulfonic derivative of formula (II).
The molar amount of Pd(0) or Ni(0) used compared with the sulfonic derivative of formula (II) ranges from 0.01 to 0.05 and is preferably 0.02.
The compound of formula (I) is generally obtained in yields  greater than 70% after filtration from the reaction mixture, addition of water, separation of the phases, evaporation of the solvent from the organic phase and drying. A further purification by crystallization or by silica gel chromatography can be carried out, if necessary.
Alternatively, the resulting compound can be saponified to give the corresponding 2-(4-methylphenyl)-benzoic acid.
The arylzinc compounds of formula (III) can be prepared, according to known techniques, starting from the corresponding aryl halides.
The sulfonic derivative of formula (II) is in its turn prepared by reaction of an alkyl salicylate of formula (IV) 
wherein R is C1-6alkyl, with a sulfonyl chloride of formula R1SO2Cl, in which R1 is as defined for compounds of formula (II), in an organic solvent and in the presence of a base.
The organic solvent used for said reaction is selected from the group consisting of optionally chlorinated aromatic hydrocarbons, C1-4alkyl acetates, C1-4 haloalkanes and aliphatic and alicyclic C1-6ketones, and mixtures thereof. Said solvent is used in amounts ranging from 1 to 10 volumes, preferably from 2 to 5 volumes, compared with compound (IV). Examples of suitable solvents are toluene, xylene, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, cyclohexanone, chlorobenzene and methylene chloride.
The reaction is usually carried out at temperatures ranging from xe2x88x9220xc2x0 to 50xc2x0 C., preferably from 0xc2x0 to 30xc2x0 C., using 1 to 2 equivalents of R1SO2Cl and 1 to 2, preferably 1.2 to 1.5, equivalents of base per equivalent of alkyil salicylate of formula (IV).
The base used in the above reaction is selected from the group consisting of oxides, hydroxides, carbonates and bicarbonates of alkali metals, such as sodium, potassium, lithium, and tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloctane.
The sulfonic derivative of formula (II) is generally obtained in yields  greater than 80% by addition of water to the reaction mixture, separation of the phases, evaporation of the organic phase and drying. The derivative of formula (II) can be purified, if necessary, by crystallization from solvents such as n-hexane, n-heptane, ligroine, methanol, ethanol, isopropanol, n-butanol, and the like.
The synthetic strategy selected for the process according to the present invention consisted in starting from inexpensive_raw materials, commercially available in large amounts and providing the formation of the biphenyl derivative through a reaction catalyzed by organometal complexes. The least expensive, commercially available benzoic derivative functionalized at the 2 position is salicylic acid and the esters thereof.
The yield and the selectivity obtained by reacting a salicylic acid sulfonic derivative with an arylzinc compound are surprisingly high in view of what reported in the prior art.
The characteristics and advantages of the process of the invention will be further evidenced by the following non limiting examples.